This application was prepared in response to RFA AA-94-06 and is designed to address the need for "more basic research using animal models on the cellular and molecular mechanisms by which alcohol acts". The principal objective will be to identify neurochemical substrates of alcohol-seeking behavior as determined by genetic and environmental variables, and thereby, to establish a "rational basis" for subsequent treatment drug selection and testing. Intracranial microdialysis combined with operant behavioral tests will be employed to study the significance of normal or abnormal function of limbic dopamine, serotonin and opioid peptide release in ethanol preference, reinforcement, and ethanol-seeking behaviors. Specific Aim 1 seeks to elucidate the neurochemical basis of genetically- determined initial ethanol preference by correlating voluntary intake with parameters of basal function and the ethanol-stimulated response profile of forebrain dopamine, serotonin, and opioid peptide release, and by contrasting results in two alcohol preferring lines of rats to that of genetically heterogeneous Wistar rats. These studies will be complemented by examination of changes in neurotransmitter function linked to preference that are induced by daily ethanol administration, as well as functional adaptations that contribute to the "switch" from the non- dependent to the dependent state. Specific Aim 2 will identify neurochemical bases of ethanol-maintained reinforcement by establishing the extent to which the neurochemical effects of ethanol in the context of voluntary self-administration differ from its direct pharmacological actions, whether a common neurochemical basis exists for the reinforcing effects of ethanol across lines of alcohol preferring rats, and whether differences in neurotransmitter responsivity to self-administered alcohol can account for differences in voluntary ethanol intake between alcohol preferring and heterogeneous Wistar rats. Specific Aim 3 will identify neurotransmitter substrates of conditioned motivational processes presumed to be involved in ethanol-seeking behavior of nondependent and postdependent animals, and to determine the neurochemical basis of differences in ethanol-seeking behavior between alcohol preferring and Wistar rats. The goal here is to identify the behavioral and neurochemical significance of environmental stimuli predictive of alcohol reinforcement and to determine whether effects of stimuli associated with the positive reinforcing actions of ethanol differ from those paired with ethanol availability during withdrawal. The neurochemical information provided by these studies can then be employed for the selection as well as the behavioral and neurochemical evaluation of promising treatment drugs. The results of this work are expected to advance the understanding of the neurochemical basis of ethanol preference as well as motivational and reinforcement processes that play important roles in sustained ethanol abuse. More importantly, this information will have direct implications for the development of effective pharmacotherapies for the treatment and prevention of ethanol abuse.